CHK1-targeted therapy to deplete DNA replication-stressed, p53-deficient, hyperdiploid colorectal cancer stem cells.
CHK1-targeted therapy to deplete DNA replication-stressed, p53-deficient, hyperdiploid colorectal cancer stem cells.
复制标题
DOI：
10.1136/gutjnl-2016-312623
复制
发表时间：
2018-05
期刊：
影响因子：
24.5
通讯作者：
De Maria R
中科院分区：
文献类型：
--
作者：
Manic G;Signore M;Sistigu A;Russo G;Corradi F;Siteni S;Musella M;Vitale S;De Angelis ML;Pallocca M;Amoreo CA;Sperati F;Di Franco S;Barresi S;Policicchio E;De Luca G;De Nicola F;Mottolese M;Zeuner A;Fanciulli M;Stassi G;Maugeri-Saccà M;Baiocchi M;Tartaglia M;Vitale I;De Maria R
癌症干细胞（CSC）负责肿瘤的形成和扩散，并且它们的靶向是根除肿瘤所必需的。晚期结直肠癌（CRC）的治疗选择有限，特别是对于携带RAS激活突变的肿瘤。本研究的目的是确定新的CSC靶向策略。为了发现作为单一药剂进行临床研究的潜在治疗剂，我们用一组FDA批准的或研究药物对从27名患者分离的富集CSC的原代CRC细胞（CRC-SC）进行了筛选。通过整合基因组、反相蛋白质微阵列（RPPA）和细胞遗传学分析鉴定候选的疗效预测生物标志物，并通过免疫染色进行验证。DNA复制应激（RS）增加，采用DNA复制干扰剂或多倍体。药物库筛选导致LY 2606368被鉴定为在相当数量的患者（约36%）的肿瘤细胞中在体外和体内起作用的强效抗CSC剂。通过抑制检查点激酶（CHK）1，LY 2606368影响了大多数CRC-SC中的DNA复制，包括RAS突变的细胞，迫使它们进入过早的致命有丝分裂。平行的基因组、RPPA和细胞遗传学分析表明，对LY 2606368敏感的CRC-SC显示出持续RS反应的迹象，包括RPA 32的磷酸化和共济失调毛细血管扩张突变的丝氨酸/苏氨酸激酶（ATM）。这与TP 53和超二倍体中的突变相关，并使这些CRC-SC精确地依赖于CHK 1功能。因此，RS的实验性增加使耐药CRC-SC对LY 2606368敏感。LY 2606368选择性消除复制应激、p53缺陷和超二倍体CRC-SC，而与RAS突变状态无关。这些结果为在CRC患者中进行生物标志物驱动的LY 2606368临床试验提供了有力的依据。
Cancer stem cells (CSCs) are responsible for tumour formation and spreading, and their targeting is required for tumour eradication. There are limited therapeutic options for advanced colorectal cancer (CRC), particularly for tumours carrying RAS-activating mutations. The aim of this study was to identify novel CSC-targeting strategies. To discover potential therapeutics to be clinically investigated as single agent, we performed a screening with a panel of FDA-approved or investigational drugs on primary CRC cells enriched for CSCs (CRC-SCs) isolated from 27 patients. Candidate predictive biomarkers of efficacy were identified by integrating genomic, reverse-phase protein microarray (RPPA) and cytogenetic analyses, and validated by immunostainings. DNA replication stress (RS) was increased by employing DNA replication-perturbing or polyploidising agents. The drug-library screening led to the identification of LY2606368 as a potent anti-CSC agent acting in vitro and in vivo in tumour cells from a considerable number of patients (∼36%). By inhibiting checkpoint kinase (CHK)1, LY2606368 affected DNA replication in most CRC-SCs, including RAS-mutated ones, forcing them into premature, lethal mitoses. Parallel genomic, RPPA and cytogenetic analyses indicated that CRC-SCs sensitive to LY2606368 displayed signs of ongoing RS response, including the phosphorylation of RPA32 and ataxia telangiectasia mutated serine/threonine kinase (ATM). This was associated with mutation(s) in TP53 and hyperdiploidy, and made these CRC-SCs exquisitely dependent on CHK1 function. Accordingly, experimental increase of RS sensitised resistant CRC-SCs to LY2606368. LY2606368 selectively eliminates replication-stressed, p53-deficient and hyperdiploid CRC-SCs independently of RAS mutational status. These results provide a strong rationale for biomarker-driven clinical trials with LY2606368 in patients with CRC.
登录
查看更多内容
影响因子：
24.5
作者：
Manic G;Signore M;Sistigu A;Russo G;Corradi F;Siteni S;Musella M;Vitale S;De Angelis ML;Pallocca M;Amoreo CA;Sperati F;Di Franco S;Barresi S;Policicchio E;De Luca G;De Nicola F;Mottolese M;Zeuner A;Fanciulli M;Stassi G;Maugeri-Saccà M;Baiocchi M;Tartaglia M;Vitale I;De Maria R
通讯作者：
De Maria R
影响因子：
64.8
作者：
Burrell RA;McClelland SE;Endesfelder D;Groth P;Weller MC;Shaikh N;Domingo E;Kanu N;Dewhurst SM;Gronroos E;Chew SK;Rowan AJ;Schenk A;Sheffer M;Howell M;Kschischo M;Behrens A;Helleday T;Bartek J;Tomlinson IP;Swanton C
通讯作者：
Swanton C
影响因子：
46.9
作者：
通讯作者：
--
影响因子：
28.2
作者：
Bardelli A;Corso S;Bertotti A;Hobor S;Valtorta E;Siravegna G;Sartore-Bianchi A;Scala E;Cassingena A;Zecchin D;Apicella M;Migliardi G;Galimi F;Lauricella C;Zanon C;Perera T;Veronese S;Corti G;Amatu A;Gambacorta M;Diaz LA Jr;Sausen M;Velculescu VE;Comoglio P;Trusolino L;Di Nicolantonio F;Giordano S;Siena S
通讯作者：
Siena S
影响因子：
45.3
作者：
Hong, David;Infante, Jeffrey;Bendell, Johanna
通讯作者：
Bendell, Johanna